Photosystem II (PSII) is a multisubunit oxidoreductase metalloprotein complex found in the thylakoid membrane of green-plant chloroplasts and internal membranes of cyanobacteria. PSII establishes the membrane pH-gradient necessary for ATP synthesis, producing dioxygen by oxidation of substrate water at the oxygen evolving complex (OEC) and plastohydroquinone by reduction and protonation of reversibly bound plastoquinone at the QB niche. Our long-term goal is to clarify fundamental aspects of catalysis at the OEC and QB redox sites, common to other metalloenzymes, including the role of active site redox events and ligand radicals as well as the problem of controlling high oxidation state metal-oxygen centers by protonation or deprotonation mechanisms. These fundamental problems are ubiquitous in metabolic mechanisms of other metalloenzymes (e.g., P-450s, peroxidases and oxygenases) common to different classes of organisms from bacteria to humans, including drug targets in cancer, antiviral, and antibacterial therapies that utilize dioxygen (or hydrogen peroxide) as a substrate. We use high-quality quantum mechanical density functional (DFT) methods and quantum mechanical/molecular mechanics (QM/MM) hybrid methods to elucidate structure/function relations in redox active sites responsible for reaction pathways as well as the regulatory role of ligand and herbicide binding, making connections with spectroscopy, mutagenesis and kinetics studies. Novel computational methods, including rigorous approaches for the description of self-consistent polarization effects associated with prosthetic groups embedded in biological molecules, a new method based on simulations of extended X-ray absorption fine structure (EXAFS) spectroscopy for structural refinement of catalytic metal clusters embedded in metalloproteins, and the combination ligand docking and scoring and QM/MM evaluation of binding affinities aim to benefit the computational community, in general.